Fruquintinib Approval Highlights Strides Made in mCRC Armamentarium in 2023

Cathy Eng, MD, FACP, FASCO

Throughout 2023, numerous advancements in the field of metastatic colorectal cancer (mCRC), including the FDA approval of fruquintinib (Fruzaqla), have helped expand the treatment armamentarium, according to Cathy Eng, MD, FACP, FASCO.

On November 8, 2023, the regulatory agency approved fruquintinib for the treatment of adult patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.¹

The decision was backed by data from the phase 3 FRESCO-2 (NCT04322539), which found that fruquintinib in combination with best supportive care (BSC) elicited a median overall survival (OS) of 7.4 months (95% CI, 6.7-8.2) vs 4.8 months (95% CI, 4.0-5.8) for placebo plus BSC (HR, 0.662; 95% CI, 0.549-0.800; P < .001).² 

“Our goal as medical providers is always to improve the survival of our patients without compromising quality of life; therefore, I feel quite confident that [fruquintinib] does provide that option for patients,” Eng explained.

In the interview with OncLive^®, Eng discussed the implications of the fruquintinib approval, as well as other key clinical trial data and regulatory decisions within the CRC realm in 2023; the importance of early molecular testing in this patient population; and the continued importance of enrolling eligible patients onto clinical trials.

Eng is the David H. Johnson Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal (GI) Cancer Research Program, a professor of medicine in Hematology and Oncology, co-director GI Oncology, vice-chair of the SWOG GI Committee, and director of the Vanderbilt-Ingram Cancer Center Young Adult Cancers Initiative at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

OncLive: How have recent data reemphasized the importance of molecular testing in patients with CRC?

Eng: Some of the highlights in CRC [from 2023 revolve around] the fact that, once again, we are very focused on molecular markers, molecular alterations, and trying to make sure that we are providing patients precision oncology as much as possible.

We want to encourage physicians, as soon as they meet a patient, to consider molecular testing because that can dramatically impact your diagnostic approach to the patient, the sequence of therapy, and enrollment to clinical trials. I'm always going to be a big advocate for [clinical trials].

What developments have been seen with KRAS G12C inhibitors in mCRC?

There are ongoing data regarding KRAS inhibitors. Some of them are still early in development. We've seen that there has been some data with the KRAS G12C [inhibitor sotorasib (Lumakras)] in combination [with panitumumab (Vectibix)], and there [have been] data [for adagrasib (Krazati) in combination with cetuximab [Erbitux)]. [The phase 3 CodeBreaK 300 trial (NCT05198934) of sotorasib plus panitumumab] presented at the 2023 ESMO Congress was a positive study.

There's a lot of interest in moving these drugs forward, possibly to the first-line setting. Also, LoxoLilly is developing its own KRAS G12C inhibitor [LY3537982]. Is the new generation [KRAS G12C] inhibitors going to be different than [prior agents]? We're very curious about that. However, keep in mind that [patients with] KRAS G12C [mutations comprise] such a small portion of our patient population, at less than 5%. We're very interested in [KRAS] G12D inhibitors, but those are still very early in development. That would also have an impact in pancreatic carcinoma.

What were some of the top highlights in CRC treatment updates in 2023?

At the 2023 Gastrointestinal Cancers Symposium,³ we saw data with trifluridine/tipiracil [TAS-102; Lonsurf] plus bevacizumab [Avastin] in [patients with refractory mCRC from the phase 3 SUNLIGHT study (NCT0437187)], and it allowed our European colleagues and those outside the United States to adopt [this strategy]. That was based upon the SUNLIGHT data, [where] in the third-line setting, [TAS-102 plus bevacizumab] improved OS vs TAS-102 alone. In the United States, [this strategy] has been largely adopted for a long time because it was already in the National Comprehensive Cancer Network Guidelines.

One study that was more of a general study that was a bit disappointing was lenvatinib [(Lenvima) in combination with] pembrolizumab [Keytruda]. [Data from] the phase 3 LEAP-017 trial [NCT04776148] were presented at the 2023 ESMO World Congress on Gastrointestinal Cancer.⁴ It did not fulfill its prespecified end point for OS, and that was a little bit disappointing. There appeared to be a hint that maybe there was more benefit in those patients without liver metastases, although that was a smaller number of patients. At the end of the day, it did not fulfill its primary endpoint for OS.

However, we've also had some other exciting aspects in regard to [current] care. We saw tucatinib [(Tukysa) plus trastuzumab (Herceptin) approved] for our HER2-positive patient population, which [accounts] for about 4% of all patients with mCRC, emphasizing the importance of molecular testing. In this case, you just want to make sure your patient is HER2 [immunohistochemistry] 2+ or 3+; those are the patients who benefit from this oral TKI. Based upon the phase 2 MOUNTAINEER trial [NCT03043313], which was a single-arm study presented at the 2022 ESMO World Congress on Gastrointestinal Cancer, [this combination] was approved by the FDA in January 2023.⁵

Now we're looking forward to seeing the results of the phase 3 MOUNTAINEER-03 trial [NCT05253651], which is [evaluating] trastuzumab plus tucatinib and mFOLFOX6 vs standard chemotherapy in newly diagnosed [patients with] HER2-positive mCRC. We want to encourage [you to look for opportunities to enroll] patients to that clinical trial.

What is the significance of the FDA approval of fruquintinib for the treatment of select patients with previously treated mCRC?

[Having] another drug for our mCRC patient population is just a huge win. In general, for providers and patients, we do not have as many treatment options as we would like in mCRC, unless you have a specific molecular alteration that is actionable, such as HER2 [positivity] or BRAF [mutations]. When you have a patient who has gone through multiple lines of therapy or doesn’t have a specific molecular marker, we need additional treatment options.

The reality is that for patients who are not surgically resectable, we need to provide them some type of therapy to improve their OS. Our [other] top goal is to not compromise their quality of life.

[Fruquintinib] provides a new opportunity for our patient population, as it appears to be well tolerated. It's an oral agent, and that's an advantage for patients as well. It has demonstrated improved OS.

How do you see fruquintinib fitting into the current mCRC treatment paradigm?

Providers will have to make that decision on their own. However, it is available in the third-line setting and beyond. It is an oral agent, which is advantageous when it's given by itself, so that may have an impact on decision making for some patients. There are going to be different adverse effects that need to be discussed with patients, and at the end of the day, it just adds into armamentarium for our patient population.

It gives a lot of hope to patients that additional drugs are being designed. So many of these newer drugs are focused on very small molecular subsets, but [some subsets account for] less than 10% of our [overall] patient population. The reality is that most of our patients need other options. Here, we hope that [fruquintinib] will give some optimism to patients about improving their OS, having good quality of life, and living their life, despite their diagnosis.

What ongoing trials could be pivotal in the advancement of the treatment landscape for patients with CRC?

[For patients harboring a] BRAF V600E mutation, there is an ongoing international trial called the phase 3 BREAKWATER study [NCT04607421], and the investigational arm is for newly diagnosed patients. That [is evaluating chemotherapy] in combination with encorafenib [Braftovi] and cetuximab [Erbitux]. [BREAKWATER] is the only phase 3 trial open globally for newly diagnosed [patients with] BRAF v600E–mutated mCRC.

There is [additional] interest right now in BRAF [mutations], as there is a new adjuvant [phase 2/3] trial [NCT05710406] for patients that test positive for BRAF mutations in the stage III setting, and that recently opened nationwide.

We still have the phase 2/3 CIRCULATE-US study [NCT05174169], which is evaluating [patients with] stage III CRC and investigating the role of circulating tumor DNA [on decisions to escalate or de-escalate treatment].

We also have recently just opened [the phase 3] EA2222 [PUMP] trial [NCT05863195], which is looking at the role of hepatic arterial infusion pump in the frontline setting [for patients with unresectable CRC liver metastases]. There is also the phase 3 ERASur study [NCT05673148], which is looking at the role of stereotactic radiation therapy or any type of liver-directed therapy other than hepatic artery infusion in a newly diagnosed patients with mCRC and liver metastases.

We once again want to encourage patients to enroll to clinical trials. These are of key importance and how we make a difference in our field. Whether it's industry-sponsored or National Cancer Institute [NCI]–sponsored, please proceed to enroll patients to clinical trials.

What is the incentive for testing patients for targetable alterations in the up-front setting?

The incentives for testing patients for molecular sequencing up-front is extremely advantageous. Number 1, it is quicker to take that specimen and analyze it before it gets sent off to storage, and then months down the line, you're trying to retrieve it. Number 2, when I talk about molecular testing, I include blood and tissue, because blood has fewer mutations to analyze. However, [blood] is also a quicker test, and it will give you a general idea of what may be possible for the patient.

Testing of the tissue with next-generation sequencing is extremely important because there are so many more molecular analyses that can be completed. It is a huge advantage for the patient because we are trying to provide them with more precision oncology. We're trying to give them care that is appropriate based upon their own molecular analysis. Understanding what mutation that they may have that may be actionable can make a big difference in how we sequence our therapies. That [information is] critical to make that decision.

When you have a patient with surgically unresectable disease, you have to think about what your plans are moving forward in regard to first-line or second-line [treatments] because you need a backup plan just in case things are proceeding in the wrong direction once treatment has been initiated. You want to have a discussion [with a patient] about what their options are down the road.

I always try to encourage individuals to enroll to clinical trials; a lot of these clinical trials now are specific to various molecular markers, which is a good thing, but [that means] the pie is getting much smaller. We're talking about patient populations of 4%, 5%, 9%, or 2% [of the overall CRC population], making it challenging for a lot of medical centers to consider opening up all these trials for [tumors with] rare mutations. However, [these studies] do make a difference for patients.

If you're out in the community and you cannot open all those small molecular subsets, we completely understand. However, [we encourage you to] reach out to the academic institutions nearby, because they are likely the ones to have a clinical trial available that you may not be able to conduct.

References

1. Takeda receives U.S. FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. Takeda. News release. November 8, 2023. Accessed November 16, 2023. https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Receives-US-FDA-Approval-of-FRUZAQLA-fruquintinib-for-Previously-Treated-Metastatic-Colorectal-Cancer/
2. Dasari NA, Lonardi S, Garcia-Carbonero R, et al. LBA25 FRESCO-2: a global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2022;33(suppl 7):S1391-S1392. doi:10.1016/j.annonc.2022.08.021
3. Tabernero J, Prager GW, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study. J Clin Oncol. 2023;41(suppl 4):4. doi:10.1200/JCO.2023.41.3_suppl.4
4. Merck and Eisai provide update on phase 3 trials of Keytruda (pembrolizumab) plus Lenvima (lenvatinib) in certain patients with advanced melanoma (LEAP-003) and metastatic colorectal cancer (LEAP-017). News release. Merck. April 7, 2023. Accessed November 16, 2023. https://www.merck.com/news/merck-and-eisai-provide-update-on-phase-3-trials-of-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-certain-patients-with-advanced-melanoma-leap-003-and-metastatic-colorectal-cance/
5. Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. January 19, 2023. Accessed November 16, 2023. https://www.businesswire.com/news/home/20221222005382/en/Seagen-Announces-FDA-Accelerated-Approval-of-TUKYSA%C2%AE-tucatinib-in-Combination-with-Trastuzumab-for-People-with-Previously-Treated-RAS-Wild-Type-HER2-Positive-Metastatic-Colorectal-Cancer